CHEST
Supplement
DIAGNOSIS AND MANAGEMENT OF LUNG CANCER, 3RD ED: ACCP GUIDELINES
The Stage Classification of Lung Cancer
Diagnosis and Management of Lung Cancer,
3rd ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines
Frank C. Detterbeck, MD, FCCP; Pieter E. Postmus, MD, PhD, FCCP;
and Lynn T. Tanoue, MD, FCCP
The current Lung Cancer Stage Classification system is the seventh edition, which took effect in
January 2010. This article reviews the definitions for the TNM descriptors and the stage grouping
in this system.
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Abbreviations: AAH 5 atypical adenomatous hyperplasia; ACCP 5 American College of Chest Physicians; AJCC 5
American Joint Committee on Cancer; BAC 5 bronchioloalveolar carcinoma; GGO 5 ground glass opacity; IASLC 5 International Association for the Study of Lung Cancer; ITC 5 isolated tumor cell; UICC 5 Union Internationale Contre le
Cancer
classification is an essential part of the approach
Stage
to patients with cancer, and there are many things
we would like to get from a stage classification. The
primary purpose of the classification is to consistently
describe the anatomic extent of disease, thus providing
a common, consistent language. The anatomic extent
of the tumor has a major impact on which treatment
we choose and what the outcome will be. However, it
is important to recognize that the stage classification
does not by itself completely define the prognosis
(which depends on multiple factors, eg, comorbidities, performance status, treatment given) or serve as
a treatment algorithm (which is driven by data from
Manuscript received September 24, 2012; revision accepted
November 30, 2012.
Affiliations: From the Yale University School of Medicine
(Dr Detterbeck), New Haven, CT; Department of Pulmonary Diseases (Dr Postmus), VU University Medical Center, Amsterdam,
The Netherlands; and Section of Pulmonary and Critical Care Medicine (Dr Tanoue), Yale School of Medicine, New Haven, CT.
Funding/Sponsors: The overall process for the development of
these guidelines, including matters pertaining to funding and conflicts of interest, are described in the methodology article.1 The
development of this guideline was supported primarily by the
American College of Chest Physicians. The lung cancer guidelines
conference was supported in part by a grant from the Lung Cancer Research Foundation. The publication and dissemination of
the guidelines was supported in part by a 2009 independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.
COI grids reflecting the conflicts of interest that were current as
of the date of the conference and voting are posted in the online
supplementary materials.
journal.publications.chestnet.org
clinical trials and treatment selection criteria). Efforts
to develop a comprehensive prognostic index system
are under way.
Stage classification is founded on the TNM system,
which dates back to 1944. Furthermore, the method
of staging is classified as clinical stage (denoted by the
prefix c) and pathologic stage (denoted by the prefix p).
Clinical stage is determined using all information
available prior to any treatment, and pathologic stage
is determined after a resection. The extent of clinical staging can vary from a clinical evaluation alone
(history and physical examination) to extensive imaging
(CT and PET scans) or invasive staging techniques.
It must be emphasized that a surgical staging procedure (eg, mediastinoscopy) is still part of clinical staging because surgical resection as a treatment has not
taken place.
Disclaimer: American College of Chest Physicians guidelines are
intended for general information only, are not medical advice, and
do not replace professional medical care and physician advice,
which always should be sought for any medical condition. The
complete disclaimer for this guideline can be accessed at http://
dx.doi.org/10.1378/chest.1435S1.
Correspondence to: Frank C. Detterbeck, MD, FCCP, Yale
School of Medicine, 330 Cedar St, PO Box 208062, New Haven,
CT 06520-8062; e-mail: [email protected]
© 2013 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.12-2354
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The Union Internationale Contre le Cancer (UICC)
and the American Joint Committee on Cancer (AJCC)
are the official bodies that define, review periodically,
and refine the stage classification systems. The current seventh edition of the lung cancer staging system was based on a major initiative undertaken by
the International Association for the Study of Lung
Cancer (IASLC). This 12-year project increased the
patient base from 5,319 (collected over several decades
predominantly at one institution) to . 100,000 (from
around the world, all cases diagnosed between 1990
and 2000).
In validating where to make a distinction between
one stage descriptor or group and another, the IASLC
required that consistent differences in prognosis had
to be seen in data sets from different continents, database types, clinical and pathologic staging, and histologic subtypes.2 Furthermore, external validation
against large databases was done. The statistical analysis was quite sophisticated; in all, the current classification is a quantum leap forward that is unequalled
by any other cancer site. However, although the database was large and involved many institutions from
20 countries, the distribution of cases was not uniform. Certain patient subgroups came predominantly
from one region or one type of database and were
treated in many different ways, and the IASLC database did not report treatment-specific outcomes.
1.0 Methods
This article addresses the official Lung Cancer Stage Classification system. Therefore, the primary sources of information
were the AJCC and UICC staging manuals.3-5 These sources were
supplemented by the publications of the IASLC International
Staging Committee, which provided the basis for the AJCC/UICC
classification,2,6-12 as well as American College of Chest Physicians
(ACCP) publications that reviewed and discussed details of the
classification.13,14
2.0 T Descriptor
2.1 Size
A detailed analysis of tumor size by the IASLC
staging committee confirmed that 3 cm was significant as a cut point; thus, the definition of T1 vs T2
was retained. In addition, significant cut points were
identified at 2, 5, and 7 cm. Therefore, subgroups were
defined for T1 (T1a and T1b) and T2 (T2a and T2b)
as shown in Figure 1. The survival differences between
each size subgroup were highly statistically significant in pathologically staged patients; among clinically staged patients, the trends were consistent but
not always significant (probably because of a more
limited data set). Tumors . 7 cm led to survival that
tracked with other definitions of T3 (ie, invasion,
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central location) and were, therefore, placed within
this group.
The size of a tumor is defined as the greatest dimension, but how this is determined is not addressed by
AJCC, UICC, or IASLC. The ACCP panel suggests
that for consistency, this measurement be done on
an axial CT image using lung windows during inspiration whenever possible (c stage); for p stage, we suggest the greatest dimension (in any direction) of the
specimen fixed after inflation or of the unfixed specimen (fixation causes about 20% shrinkage).15 Further
issues arise with semisolid or ground glass opacities (GGOs), which have not been addressed by the
AJCC or UICC. One can measure the solid or the
ground glass component with either mediastinal or
lung windows on a CT image. Emerging data suggest that the size of the solid (invasive) component
is of greater prognostic value than the ground glass
(lepidic) component.16-22 The ACCP panel suggests
recording the size of both the GGO and the solid
component on lung windows (or the percent solid
by area) for c stage and both the entire tumor (including lepidic portions) and the invasive component for
p stage.14 This suggestion is consistent with a recent
UICC supplement handbook.5
2.2 Invasion
There were insufficient numbers of patients for
whom reliable data were available to investigate the
validity of other traditional T2, T3, or T4 descriptors
(visceral pleural invasion, central location within a
lobar or mainstem bronchus, partial or complete atelectasis, direct invasion of particular structures, etc).
These traditional definitions were retained even though
they could not be confirmed because there were no
data to suggest that they are not valid.
Invasion beyond the elastic layer of the pleura is
defined as T2, including invasion into an adjacent
lobe. Elastin stains should be used whenever there is
ambiguity.23 T3 includes invasion into the parietal
or mediastinal pleura or the parietal pericardium.
T4 includes invasion of the visceral (inner) pericardial surface and the intrapericardial pulmonary artery
and pulmonary veins. Involvement of either the intrapericardial or extrapericardial vena cava or aorta
is considered T4. We suggest that involvement of
the azygous vein be classified as T3 because it is
not counted among the great vessels (but this is not
addressed by IASLC, AJCC, or UICC).
A Pancoast tumor is classified as T4 if there is
unequivocal involvement of C8 or higher nerve roots,
cords of the brachial plexus, subclavian vessels, vertebral bodies, lamina, or spinal canal. The tumor is classified as T3 if it involves only thoracic nerve roots
(eg, T1 or T2 nerve roots).
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Figure 1. [Sections 2.0, 3.0, 6.2] Definitions for TNM descriptors. Adapted with permission from Detterbeck et al.13
*These subgroup labels are not defined in the IASLC publications7-10 but are added here to facilitate a clear discussion.
†In the greatest dimension.
‡T2 tumors with these features are classified as T2a if ⱕ 5 cm.
§The uncommon superficial spreading tumor in central airways is classified as T1.
Pleural effusions are excluded that are cytologically negative, nonbloody, transudative, and clinically judged not to be due to cancer.
Left-side recurrent laryngeal nerve paralysis is classified as T4 when directly invaded by the primary
tumor but as N2 when invaded by nodal disease. Similarly, infiltration of the superior vena cava, trachea, or
esophagus by the primary tumor is defined as T4
but as N2 or N3 when infiltration emanates from the
lymph nodes.
Difficulties arise in the classification of mediastinal
invasion. Although mediastinal pleural invasion is classified as T3, mediastinal fat invasion is T4, and parietal pericardial invasion is T3. Because there is usually
some fat between the mediastinal pleura and the
pericardium, this classification is confusing. Furthermore, differentiation between hilar fat (considered T2)
and mediastinal fat (T4) is difficult. The ACCP panel
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suggests that only unambiguous mediastinal fat involvement be used as a criterion for T4 status (eg, extensive replacement by tumor on CT scan); otherwise,
the lower T3 classification should be chosen.14
3.0 N Descriptor
Analysis of the prognostic influence of the N descriptor resoundingly supported the traditional categorization of N0, N1, N2, and N3; therefore, these definitions
were carried forward (Fig 1).8 Direct extension of
a primary tumor into a node is classified as nodal
involvement. Station 1 nodes are classified as supraclavicular nodes, which include the low cervical
nodes, caudal to the lower margin of the cricoid (N3).
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Extrathoracic node involvement is designated as M1b
(eg, a positive axillary node).
Further analyses were done to explore whether
particular node stations within an N category had
any particular impact. No such relationship could be
identified (Fig 2).8 Specifically, there was no difference in survival among patients with involvement of
only peripheral N1 nodes or hilar N1 nodes, and no
difference based on which N2 nodal stations were
involved. This was true globally as well as within geographic regions. Survival among patients with pN2
right upper lobe tumors with and without N1 involvement (skip metastases) was not different, although
there was a slight difference among such patients
with a left upper lobe tumor.8
The IASLC staging committee developed a new
node map24 to overcome ambiguities arising from discrepancies between previous node maps in use in different geographic regions. Furthermore, the committee
defined several nodal zones as follows: a supraclavicular zone (station 1), an upper zone (stations 2-4), an
aortopulmonary zone (stations 5 and 6), a subcarinal zone (station 7), a lower zone (stations 8 and 9),
a hilar zone (stations 10 and 11), and a peripheral zone
(stations 12-14). There were no differences in prognosis among involvement of different nodal zones
within the N1 or N2 category. Specifically, there was
no difference between patients with a left upper lobe
tumor and involvement of nodes only in station 5 and
6 and patients with a tumor in a different lobe and
involvement of another single N2 nodal zone.8
The number of involved nodal zones appeared to
have a prognostic impact. Patients with pathologic
single-zone N1 involvement had better survival than
those with pathologic multizone N1 involvement (5-year
survival, 48% vs 35%; P , .09). Similarly, patients
with pathologic single-zone N2 involvement had better
survival than those with pathologic multizone N2
involvement (5-year survival, 34% vs 20%; P , .001).
In fact, the survival curves of patients with pathologic
multizone N1 and single-zone N2 involvement were
almost superimposed.8 However, the prognostic impact
of the number of pathologic nodal zones involved
could not be validated within T-stage categories and
by geographical region, type of databases, or clinical
staging because the number of patients in the subsets
was too small.8 Therefore, the IASLC staging committee decided against subdivision of N categories.
The prognostic impact of nodal involvement by direct
extension of a primary tumor also could not be validated through the IASLC database because of insufficient sample sizes but was retained because it is
consistent with general UICC and AJCC rules.
3.1 Node Map
The IASLC node map is shown in Figures 3 and 4.
Important features include better definition of the
subcarinal zone as extending down to the level of
origin of the left lower lobe and right middle lobe
bronchus.24 The border between left- and right-side
paratracheal nodes is the left lateral border of the trachea (not the midline). The 4R nodal area extends
from the lower border of the left innominate vein to
the lower border of the azygous vein; the 4L nodal
region extends from the level of the top of the aortic
arch to the upper border of the left-side pulmonary
artery medial to the ligamentum. The level 2 regions
extend from the border of level 4 to the upper border
of the manubrium in the midline. The supraclavicular nodes extend from the lower border of the clavicles to the lower border of the cricoid. Further details
and definitions of all the node stations can be found
in Rusch et al.24
3.2 Criteria for Pathologic N Assessment
Figure 2. [Section 3.0] Median survival (mo) of patients in the
International Association for the Study of Lung Cancer database with
single lymph node zone involvement.8 NS 5 not significant.
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The following comments apply to nodal staging at
the time of resection. Issues regarding clinical (pretreatment) staging are discussed in section 7.0 of this
article, “Type of Stage Classification.”
A general AJCC/UICC recommendation is that at
least six lymph nodes/stations be sampled for pathologic node staging. The IASLC manual recommends
that three mediastinal (including level 7) and three
N1 nodes/stations be sampled. Whether the number
is supposed to apply to node stations or individual
nodes is undefined. Moreover, the pathologist cannot
distinguish six nodal fragments from six separate
nodes (unless the surgeon is meticulous in how nodes
and fragments are labeled and submitted). However,
the IASLC staging committee encourages systematic
intraoperative node assessment as recommended by
clinical guidelines.25,26
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Figure 3. [Section 3.1] The International Association for the Study of Lung Cancer lymph node map,
including the proposed grouping of lymph node stations into zones for the purposes of prognostic analyses. Ao 5 aorta; Eso 5 esophagus; L 5 left side; mPA 5 main pulmonary artery; R 5 right side; SVC 5
superior vena cava; T 5 trachea. Reproduced with permission from Rusch et al.24
Furthermore, the definition of number of nodes/stations needed for pathologic staging by IASLC and
AJCC is confusing. If all nodes are negative, the tumor
is defined as pN0, regardless of the number sampled, yet if some are positive, it is implied that only
cN status be used if fewer than six nodes/stations
were sampled. To avoid this awkward inconsistency,
the ACCP panel endorses the suggestion14 that whenjournal.publications.chestnet.org
ever fewer than six nodes/stations are sampled at
resection, the tumor is classified as pN0, pN1, or pN2
with the uncertainty descriptor [eg, pN0(un)], as is
described in section 8.0 of this article, “Additional
Descriptors.” This descriptor has been suggested by
IASLC for further testing relative to the completeness of resection (R) classification; however, extrapolation to address an inconsistency in the formal rules
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Figure 4. [Section 3.1] A-F, Illustrations of how the International Association for the Study of Lung Cancer
lymph node map can be applied to clinical staging by CT scan in axial (A-C), coronal (D), and sagittal
(E, F) views. A and B, The border between the right- and left-side paratracheal region is shown. Az 5 azygous vein; InV 5 innominate vein; LLLB 5 left lower lobe bronchus; Lt 5 left; MB 5 mainstem bronchus; PA 5 pulmonary artery; Rt 5 right; SCA 5 subclavian artery; SPV 5 superior pulmonary vein. See
Figure 2 legend for expansion of other abbreviations. Reproduced with permission from Rusch et al.24
regarding the definition of pN status seems reasonable to the panel.
Biopsy of only one sentinel node is considered
adequate and is denoted as pN0(sn) if findings are
negative and pN1-3(sn) if positive, reflecting the level
of the sentinel node. However, sentinel node identification in lung cancer is variable and not widely
practiced.27-29
4.0 M Descriptor
The new stage classification system no longer recognizes the term MX because clinical staging information is always available. A history and physical
examination are critical parts of clinical staging and
often are very reliable without further imaging or
biopsy.
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The presence of distant metastases is classified as
M1b.9 Slightly worse survival was seen in patients
with multiple vs a solitary distant metastasis (median
survival, 5 months vs 6 months; 1 year survival, 20%
vs 23%; P 5 0,006).9 No differences were noted by
the site of a solitary distant metastasis except slightly
shorter survival for a solitary brain metastasis. However, the data set was too limited for adequate validation, and further subdivision of the M1b category was
not undertaken.9
Pleural (or pericardial) involvement (either multiple implants or a malignant effusion) is classified as
M1a because of slightly better survival than for distant metastatic sites and worse survival than for other
categories of T4.9 These prognostic differences were
highly statistically significant and held up to internal validation (across database types and geographic
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regions) as well as external validation (ie, the Surveillance Epidemiology and End Results [SEER] database).9
The IASLC, AJCC, and UICC manuals are confusing about whether M1a applies to only the ipsilateral
pleura or also to the contralateral pleura14; the ACCP
panel suggests that it apply to both.
Figure 6. [Section 5.0] TNM elements included in stage groups.
Adapted with permission from Detterbeck et al.13
5.0 Stage Grouping
The IASLC staging committee defined stage groupings (Figs 5, 6). Despite the recognition of many new
subdivisions of the T and M descriptors, the stage
grouping has no new subdivisions. However, the definition of the stage groups has become more complex because of the additional T and M descriptor
subgroups. An online tool to manage the complexity
and to assist in on-the-spot definition of a tumor’s
stage is available at http://staginglungcancer.org.30
Illustrations of the TNM categories and subcategories included within each stage group are shown
in Figures 7 to 9.
6.0 Additional Tumor Nodules and
Multiple Primary Lung Cancers
The classification of patients with additional tumor
nodules has created confusion largely related to a lack
of appreciation of distinctly different categories of
such nodules. Applying a classification system intended
for one category to a different group has the potential
to lead to suboptimal treatment and outcomes.
The first category involves patients with a newly
found lung cancer who have another (small) nodule
detected by imaging. The majority (about 75%) of
additional pulmonary nodules seen on CT imaging in
patients with potentially operable cI to cIIIa primary
lung cancer are benign (see “Evaluation of Individuals
Figure 5. [Section 5.0] Stage groups according to TNM
descriptor and subgroups. Reproduced with permission from
Detterbeck et al.13
*Percentage of patients in IASLC database according to best stage
(rounded to nearest integer).10
With Pulmonary Nodules: When Is It Lung Cancer?” by Gould et al31 in the ACCP Lung Cancer
Guidelines).32-35 An expert panel (ie, a multidisciplinary
tumor board that includes chest radiology, thoracic
surgery, and pulmonary medicine) usually can arrive
at a strong consensus about most of these lesions.36
Although firm data are lacking, experience suggests
that the judgment is seldom wrong when such an
informed review deems an additional nodule to most
likely be benign.36
A second category involves patients with an advanced
primary cancer (most often also with nodal involvement) who have several pulmonary nodules or a single
pulmonary nodule and other sites that appear typical for distant metastases. Again, the judgment of
a tumor board that the additional nodules in such a
presentation represent metastatic disease is rarely
called into question by the subsequent course of the
disease (although specific data documenting this
are lacking).
6.1 Second Primary Lung Cancers
Occasionally, patients with a typical clinical presentation of a lung cancer (ie, a solid, spiculated mass in
a patient with lung cancer risk factors) also exhibit a
second lesion with such a typical appearance (either
synchronously or metachronously). In fact, the incidence of a second primary lung cancer has been consistently found to be approximately 1.5% to 2% per
patient per year.37-47 Traditionally, this group has been
defined by a clinical team guided by criteria developed empirically by Martini and Melamed48 in 1975
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Figure 7. [Section 5.0] Graphic illustration of stages 0, I, and II. Reproduced with permission from
Detterbeck et al.13
and more recently refined by the ACCP using indirect data (Fig 10).34,49 The majority of tumors classified in this way have been of the same histologic
type,37,41,42,50-61 which is logical because the etiology of
both cancers is likely the same (ie, genetic predisposition, environmental exposures). Furthermore, similar
survival results have consistently been found whether
the histologic type is the same or different,51-55,58,60-66
suggesting that the traditional definition of second
primary lung cancers based on clinical features (as
opposed to one based only on different histology) is
generally correct.
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The IASLC staging committee puts the responsibility of identifying second primary lung cancers
squarely on the pathologist.6 However, defining second primary lung cancers primarily by histologic features is problematic for several reasons. First, this
deviates from the definition that has been in use,
thereby defining patients differently moving forward
than what was done in the IASLC database. Second,
this creates tremendous pressure to use genetic and
morphologic characteristics that are not yet standardized or validated. Finally, pathologic assessment has
primarily involved resected specimens, yet clinical
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Figure 8. [Section 5.0] Graphic illustration of stages IIIA and IIIB. Reproduced with permission from
Detterbeck et al.13
management necessitates a preoperative definition. The
applicability of postoperative data to limited biopsy
specimens is poorly defined.
Differentiation of adenocarcinomas (in resected
specimens) by the percentage of morphologic patterns (eg, acinar, papillary) has been proposed.16,19,22,66-70
Definition of second primary lung cancers by genetic
characteristics has produced conflicting results so
far.71-77 How valid these measures are in differentiating a second primary lung cancer from a metastasis
requires further study, and whether these techniques
can be applied to small biopsy specimens is unclear.
The AJCC, UICC, and IASLC rules are confusing
with regard to stage classification. The IASLC stated
that “multiple synchronous primary tumors should
be staged separately.”6 However, the next sentence
states, “The highest T category and stage of disease
should be assigned and the multiplicity of the number of tumors should be indicated in parenthesis,
e.g. T2(m) or T2(5).”6 It seems contradictory that separate staging can be achieved by combining all tumors
under one TNM designation. The AJCC specified that
this multiple tumor classification T(m) applies to tumors
of the same histology,4 but the IASLC implied that
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the T(m) NM classification be used even with different histologic types.6 The UICC 2010 manual did not
comment on this,3 but the 2012 supplement manual
stated, “A tumor in the same organ with a different
histologic type is counted as a new tumor.”5 Finally,
the AJCC manual stated that in “simultaneous bilateral cancers in paired organs, the tumors are classified
separately as independent tumors in different organs,”4
with essentially the same wording used by UICC and
IASLC.3,6 Whether this means a TNM designation for
each one or for both together is not explained. Furthermore, there is confusion about whether the lungs
are considered together as one organ or two paired
organs (unclear in AJCC but clearly listed as a paired
single organ by UICC).3,4
Therefore, the ACCP panel endorses the suggestion that second primary lung cancers be defined by
an experienced multidisciplinary team,14 using collective judgment and considering all information (including
the imaging, risk factors, suspicion of distant dissemination, and the pathologist’s confidence given the
available specimens). A careful evaluation for distant
and mediastinal metastases is strongly recommended
(see the articles “Methods for Staging Non-small Cell
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Figure 9. [Section 5.0] Graphic illustration of stage IV. Reproduced with permission from Detterbeck et al.13
Figure 10. [Section 6.1] Definition of multiple primary lung
cancers.
Lung Cancer” by Silvestri et al78 and “Treatment of
Small Cell Lung Cancer” by Jett et al79 in the ACCP
Lung Cancer Guidelines). A regional dedicated thoracic oncology team should be consulted if not available locally.
In addition, with the hope that this will reduce confusion, the ACCP panel recommends that when two
lung cancers with a typical appearance (solid, spiculated, or lobulated) are deemed to be synchronous
primary cancers, they be classified with a TNM descriptor for each tumor. The combined T(m) classification
should be reserved for multifocal tumors (usually
more than two) that typically have a GGO appearance (as discussed in section 6.3).
6.2 Additional Pulmonary Tumor Nodules
The IASLC database contains cases of lung cancer
with additional pulmonary tumor nodules of cancer,
accounting for a small portion (2.5%) of the database.
Second primary lung cancers and metastatic disease
(M1) were specifically excluded from this category;
however, there is no information regarding how the
contributing centers defined such additional nodule
cases beyond this.
Because of similar relative survival differences,
these nodules were classified within the T3, T4, and
M1a descriptor cohorts if they were located in the
same lobe, an ipsilaterally different lobe, or the contralateral lung, respectively (ie, T3Satell, T4Ipsi Nod, and
M1aContr Nod in Fig 1). Because of conflicting definitions in the IASLC and AJCC manuals, it is unclear
whether the additional tumor nodule designation is
meant to apply only to lesions that can be recognized grossly or also to lesions detected solely by the
pathologist.4-6
It has been suggested that the IASLC stage classification of additional pulmonary tumor nodules T(m)
be used for patients with a dominant classic lung cancer (ie, solid, spiculated) who have an additional nodule with similar radiographic and histologic features.14
The ACCP panel endorses this definition and suggests
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that the additional nodule classification also applies to
lesions that are not clinically apparent. It is not clear
that this definition matches the cases included in the
IASLC database. The database may have included
some multifocal, predominantly GGO lesions because
this cohort included mostly cases from Asia2 (where
such tumors appear to becoming more common),80,81
although the fact that the IASLC database includes
only cases from 1990 to 2000 probably diminishes
this effect because the detection of GGO lesions
appears to have been less common during this period.
It is important to note that the IASLC database
does not clearly define the prognosis of patients with
additional nodules that are encountered clinically today.
First, the definitions used in the IASLC database for
this cohort are unclear. Second, the prognosis varies
significantly among geographic regions and types of
databases. Finally, treatment was not accounted for
in the analysis yet varied markedly (96% and 88% of
T3Satell and T4Ipsi Nod, respectively, were managed surgically vs 2% of M1aContr Nod).2,7,9 In fact, patients with
additional tumor nodules who underwent resection
exhibited good 5-year survival (45% for T3Satell N0 M0
R0, 48% for pT4Ipsi Nod N0 M0 R0).7
6.3 Multiple (Multifocal) Lung Cancers
Multifocal disease is well recognized for bronchioloalveolar carcinoma (BAC)82-84; however, because
the term BAC was used in different ways, its use has
been abandoned.19 Although the term BAC has been
retired, patients are still seen with multiple foci of such
tumors. The spectrum of lesions that were included
under the rubric of BAC included newly defined histologic entities (ie, adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant
adenocarcinoma)19; the nature and relationship of these
lesions to one another is not yet well understood.19,21,83-90
These factors have led to confusion about how to
classify multifocal disease, which is exacerbated by
wording in the stage classification manuals that can
be interpreted in different ways. Such multifocal
tumors (ie, what would formerly have been called
multifocal BAC) currently are variably classified as
multiple distant metastases, synchronous second primary cancers, and additional nodules. A more uniform classification is needed, or the data collected
will be uninterpretable.
The ACCP panel endorses the suggestion that the
T(m) designation be used for patients with multifocal
lung cancer, meaning patients with several GGO
lesions that are malignant or contain numerous small
foci.14 The AJCC and UICC rules suggest that multiple simultaneous tumors be classified by the highest
T stage of one focus with the number of tumors in
parentheses.3,4 For example, a patient with four GGO
journal.publications.chestnet.org
lesions all measuring , 2 cm would be classified as
having T1a(4) disease. In this classification category,
the N and M designations apply to all the multiple tumor foci. The T(m) designation should only be
applied to lesions that are either proven or strongly
suspected to be malignant, that is, not atypical adenomatous hyperplasia (AAH) lesions. This appears to
be consistent with the intent of the T(m) designation
according to the IASLC manual, which specifically
mentions the common occurrence of multiple foci
of BAC tumors.
The ACCP panel defines multifocal lung cancers as
multiple GGO lesions, which may, however, develop
a solid component.62,83,87,91,92 There may be a few
or many lesions.92 We include patients with such a
malignant GGO lesion (either suspected or proven)
and other small GGO lesions that are likely AAH
because data suggest that AAH is a precursor to such
tumors.21,83-89,93,94 Including such patients also satisfies the need for a clinically applicable definition.
At the other end of the spectrum are patients with an
infiltrative pattern of disease confined to a particular area (segment or lobe) or appearing diffusely in
the lung parenchyma (also called pneumonic type
of adenocarcinoma).62,95,96 These lesions should also
be included among multifocal cancers.
Multifocal cancers appear to have a decreased propensity for nodal or systemic spread and an increased propensity to develop additional pulmonary foci.62,83,87,91,97
This feature seems to fit with what was intended by
the T(m) nomenclature, which designates multiple
tumors in the T descriptor but maintains a composite
N and M designation that applies to all the multiple
tumors in aggregate. Further study of this form of
lung cancer is needed. Nevertheless, adoption of a
classification nomenclature, even if imperfect, will
facilitate such research by more precisely identifying
a specific and homogeneous population.
7.0 Type of Stage Classification
The main stage classification types are clinical and
pathologic (Fig 11). According to the AJCC manual,4
clinical stage (pretreatment classification) encompasses “any information obtained…before initiation
of definitive treatment,” incorporating symptoms and
Figure 11. [Section 7.0] Types of staging assessments.
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physical examination; imaging; endoscopy; biopsy;
and surgical staging procedures, including exploration. The pathologic stage (postsurgical classification)
includes information from the clinical stage supplemented by “information obtained…through completion
of definitive surgery.”4 Other stage classification types
(Fig 11) include restaging after induction treatment
(designated yc or yp), staging when recurrence develops
(designated by r), or staging at autopsy (designated
by a). Although pathologic stage is more accurate,
clinical stage is what is available when treatment
decisions are made.
Complexity arises because the AJCC allows clinical and pathologic classification to be applied to individual T, N, and M descriptors and allows use of
individual pT and pN descriptors outside the setting
of (intended) surgical resection.4 This creates confusion because procedures explicitly classified as clinical staging nevertheless yield results that can define
a pT or pN descriptor, and the overall classification
can be a mixture of clinical or pathologic individual T,
N, and M descriptors. Note that the UICC and IASLC
do not recognize this individual p designation outside the setting of a surgical resection (or attempted
resection).
Definition of pT status outside the setting of
attempted resection requires biopsy specimen proof
of invasion to confirm the highest T category. Practically speaking, such a clinical determination of pT is
rare but might include biopsy specimen proof of carinal involvement (or potentially an excisional wedge
resection specimen that defines the largest tumor
dimension yet was not intended as a therapeutic procedure). The designation of pM can be used when
there is biopsy specimen proof of a distant (or pleural/pericardial) metastasis; however, a pM0 designation does not exist, even if a biopsy is done (only cM0).
AJCC definition of pN outside the setting of
attempted resection is particularly problematic.98,99
This requires one of the following: (1) biopsy specimen proof of N3; (2) all nodes with negative biopsy
specimen findings, regardless of number sampled
(presumably at least 1); (3) any microscopic evaluation of nodes if pT status is defined; or (4) a sentinel
node biopsy specimen and definition of pT status.
Thus, although endobronchial ultrasound or mediastinoscopy explicitly comprise clinical staging, the
result can be viewed as defining a pN status.
Complex rules govern assignment of an overall clinical or pathologic designation to a mixture of individual descriptors (eg, cT1pN3cM1, pT2cN0cM1,
cT2cN0pM1). In the absence of resection, the overall
classification is pathologic if (1) an M1 biopsy specimen finding is positive (ie, cTcNpM1), (2) an N3
biopsy specimen finding (the highest N category) is
positive (ie, cTpN3cM0), or (3) the T stage is cone202S
firmed by biopsy specimen and nodal involvement
at any level is confirmed (ie, pT1-4pN1-3cM0). All other
combinations of cT, pT, cN, pN, and cM define an overall clinical stage. The definition is awkward in a nonresectional setting because pN0 is unacceptable for
defining overall pathologic stage (eg, pT1-4pN1-3cM0
is classified as pathologic, whereas pT1-4pN0cM0
is clinical). Presumably, these rules pertain only to
patients with unresected lesions; otherwise, clinical
staging would apply to all with N0, even if resected,
including a complete lymphadenectomy.
The AJCC staging rules are ambiguous and appear
to allow for several approaches. The approach that
avoids the confusion and ambiguity arising from the
others is to restrict pathologic staging to the postresection stage (or rarely an aborted resection with extensive biopsy specimens). Pretreatment staging remains
clinical; if such staging involves biopsy specimens,
the UICC rules allow for the use of cT, cN, or cM
along with a certainty factor classification (eg, cN2C3)
rather than pT or pN. The C designation is described
in the next section and summarized in Figure 12.
This approach is suggested by the ACCP panel.
8.0 Additional Descriptors
8.1 Certainty Factor
The UICC has defined an optional C factor (Fig 12)
to denote the extent of investigation performed to
establish the stage designation (ie, clinical evaluation,
imaging and needle aspiration, surgical staging, resection). This factor can be applied to the entire stage
or to individual T, N, and M descriptors. This factor
carries the misleading name of certainty, implying
that certainty is related primarily to the specific technique, whereas in reality, the clinical setting is most
important (eg, a normal mediastinum on PET scan
has a false-negative rate of , 5% for peripheral cI
tumors vs about 25% for central tumors).100,101 Furthermore, the thoroughness of staging procedures varies greatly.102
8.2 Completeness of Resection
The completeness of resection (radicality) is more
clearly defined in the new system (Fig 12). A positive
margin includes nodal margins and positive pleural
or pericardial fluid cytology. According to suggestive individual studies, several new classifications
will be tested, including pleural or pericardial lavage
cytology, highest mediastinal node involvement, or
nodal classification based on a limited assessment.
Additional descriptors have been developed for the
depth of visceral pleural invasion, chest wall invasion,
lymphatic and vascular invasion, and the number of
nodal zones involved.14
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Figure 12. [Sections 7.0, 8.0] Additional descriptors.
The classification can also be applied to distant metastatic sites (M0). Nonmorphologic techniques include DNA or RNA analysis or flow cytometry.
CXR 5 chest radiograph; ITC 5 isolated tumor cell.
aIn greatest dimension.
8.3 Minimal Disease
Sophisticated immunohistochemical and genetic
techniques permit detection of very small tumor
deposits (Fig 12). A micrometastasis as defined by
the UICC and AJCC3,4 is 0.2 to 2 mm in size and
usually is detected by routine hematoxylin and eosin
staining; typically, mitoses and invasion are seen.103
Such micrometastases in nodes or distant sites are
counted as positive and denoted by the symbol (mi)
[eg cN1(mi), pN2(mi)]. However, the prognostic impact
was not evaluated in the IASLC staging analysis.
Isolated tumor cells (ITCs) are small clumps of
tumor cells (, 0.2 mm), typically without mitoses or
vascular or lymphatic invasion. ITCs within nodes (or
distant sites) are not counted in the stage classificajournal.publications.chestnet.org
tion and should be coded as N0 (or M0), regardless of node level harboring the ITCs [eg, pN0(i1),
pN0(mol1)]. The prognostic value of ITCs has been
inconsistent.104-109
9.0 Applicability to Different
Lung Cancer Types
The seventh edition of the Lung Cancer Stage
Classification is applicable to all major types of primary lung cancer. The system was developed based
on non-small cell lung cancer; however, validation
studies in patients with small cell lung cancer11 and
carcinoid tumors12 have demonstrated that the definitions are also of value in these cohorts. Therefore,
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Figure 13. [Section 10.0] Median survival (mo) of the clinical
T descriptor cohort (cN0, cM0) in the International Association for
the Study of Lung Cancer database according to the geographic
region and database type. Aus 5 Australia; Clin 5 clinical.2
the stage classification should be applied to patients
with these tumors as well.
10.0 Discussion
The purpose of the stage classification system is
to provide a nomenclature to describe the anatomic
extent of disease. In the past, the descriptors and
groupings have been based largely on what seemed
to be logical; in the current seventh edition, this is
based on extensive statistical analysis. The basis for
deciding that a particular cut point or definition was a
good criterion to distinguish one group from another
was a difference in prognosis between the groups
that was consistent in multiple subset analyses (geoFigure 14. [Section 10.0] Median survival (mo) of the clinical N
descriptor cohort (cTAny, cM0) in the International Association
for the Study of Lung Cancer database according to the geographic region and database type. See Figure 13 legend for expansion of abbreviations.2
e204S
graphic, histologic, database type, time period, clinical
or pathologic) as well as in external validation (ie, Surveillance Epidemiology and End Results database).
Thus, prognosis was used as a tool in the analysis,
and differences in prognosis were the end points of
analysis.
How do we use the staging nomenclature? A clinical need is to select the optimal treatment of patients,
and the anatomic extent of disease is certainly a major
factor in the treatment selection. However, we cannot
expect the stage classification to serve as a treatment
algorithm. First, many other factors affect the treatment selection, including functional status, comorbidities, histology, and personal factors. Second, the
criterion used to separate or group patients was not
whether current guidelines recommended treatment
that was the same or different. Finally, progress in
defining optimal treatment should be continuous and
informed by the results of clinical trials. Stage classification is relatively static, updated every 7 or 8 years
when a new edition is produced. Thus, the stage
classification is useful in describing one factor related
to choosing a treatment strategy and in assessing
whether the results of a clinical trial may be applicable
to a particular patient, but it does not by itself define
a treatment approach.
Another clinical need is to define prognosis. Again,
the anatomic extent of disease is an important factor
that contributes to prognosis. However, there are
Figure 15. [Section 10.0] Treatment given (as percentage of
total) in NCDB (2004-2007) to patients with non-small cell lung
cancer (n 5 22,044) whose stage grouping shifted from the designation in the sixth to the seventh edition of the Lung Cancer Stage
Classification system. Ch 5 chemotherapy; ChRT 5 chemoradiotherapy; ChRT-S 5 chemoradiotherapy then surgery; Ch-S 5 chemotherapy then surgery; NCDB 5 National Cancer Database; No
Tmt 5 no treatment; RT 5 radiotherapy; S 5 surgery alone; S-Ch 5
surgery then chemotherapy; S-ChRT 5 surgery then chemoradiotherapy; S-RT 5 surgery then radiotherapy. See Figure 4 legend
for expansion of other abbreviations. Reproduced with permission from Boffa et al.110
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many other prognostic factors, including those related
to the tumor, patient, treatment, and clinical and social
setting. There is a need for a prognostication tool that
takes these factors into account, and it is often suggested that the stage classification be modified to include
other factors (eg, shifting stage grouping up or down
depending on patient age or other factors). However,
prognostication is extremely complex, and such an
approach is overly simplistic. For example, certain
factors may be highly significant if a particular treatment is given but have little relevance in other settings. Therefore, acknowledging only a few prognostic
factors and adjusting the TNM stage would be insufficient to define prognosis yet could tremendously
complicate use of the TNM system; it is best to separate prognostication from anatomic disease description and allow time for development of a sophisticated
prognostication tool.
We need to be careful in applying prognostic data
from the IASLC database. It is true that this database
is the largest available and defines prognosis for patients
with a certain anatomic extent of disease from around
the world, but there were marked differences in prognosis in different geographic regions and by database type (Figs 13, 14), and which region or database
type was better varied between T and N categories. It
is not clear why prognosis varied so much; no consistent factor has been identified, although many have
Figure 16. [Section 11.0] ACCP suggestions to avoid ambiguities in the IASLC, UICC, and AJCC stage classification systems.
ACCP 5 American College of Chest Physicians; AJCC 5 American Joint Committee on Cancer; GGO 5 ground glass opacity; IASLC 5 International
Association for the Study of Lung Cancer; UICC 5 Union Internationale Contre le Cancer.
aExplicitly defined by AJCC or UICC, listed here nevertheless because of common lack of awareness of this.
bImplied by AJCC or UICC.
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been suggested (eg, genetic variation, such as the
frequency of epidermal growth factor receptor mutations or differences in the proportion of nonsmokers
in different regions). Furthermore, the treatment
given was not accounted for or validated in the IASLC
database. A comparison of what treatment was given
in the US National Cancer Database (which does have
validated treatment data) for those cohorts whose
stage grouping changed from the sixth to the seventh
edition shows marked variation (Fig 15). Therefore,
we must acknowledge that the IASLC database does
not precisely define the prognosis for a particular
patient, and we certainly cannot assume that it has
defined the prognosis for a particular treatment
approach.
We must be particularly careful in the use of prognosis to guide decisions about treatment. The fact that
survival is poor does not necessarily imply that it is
worth adding further therapy (eg, adjuvant chemotherapy); what we really need is data demonstrating
that additional treatment actually improves survival.
At the same time, we should not rule out a particular
approach just because (our perception of) prognosis
is poor. In the IASLC database, patients with pleural
involvement or with ipsilaterally different lobe nodules who underwent resection actually had good survival (5-year survival, 31% if pTAny N0 M1aPl Dissem R0
and 48% for pT4Ipsi Nod N0 M0 R0).7 The patients who
underwent resection, of course, represent a selected
subgroup. However, these observations illustrate how
the interplay among clinical and pathologic staging,
treatment approach, and patient selection can influence our perception of similar outcomes.
Although the stage groupings are a reasonable way
to group patients and are based on a sound statistical
analysis, this does not prove that the tumor biology is
homogeneous. For example, the survival curves of
patients with T4Inv and T4Ipsi Nod tumors do not necessarily track together, suggesting that there may be
biologic differences. Certainly, there are groups that
have a similar prognosis but markedly different clinical characteristics (eg, stage IIIA includes patients
with N2 disease [T1-3 N2 M0], those with extensive
local invasion only [T4Inv N0 M0], and those with ipsilateral additional tumor nodules [T4Ipsi Nod N0 M0]).
We must view stage classification as a useful tool that
may well change over time as our understanding and
treatment outcomes evolve.
11.0 Conclusion
There is no question that the IASLC staging classification is a major advance. The size of the database,
the broad international spectrum, the careful and
detailed analysis, and the internal and external validation are tremendous achievements and relatively
e206S
unique among types of cancer. Inevitably, it is also
more complex, and with more refined data comes a
greater ability to discern granular details. As with any
complex system, rules that seem clear in one context
can seem awkward or conflicting in another. This article reviews the fundamental definitions as well as
suggested approaches that minimize the conflicts in
those cases where ambiguous rules create confusion (Fig 16). A thorough understanding of the stage
classification is essential because it is fundamental
to our ability to converse clearly about patients with
cancer.
Acknowledgments
Author contributions: Dr Detterbeck had full access to all of
the data in the study and takes responsibility for the integrity of
the data and the accuracy of the data analysis.
Dr Detterbeck: contributed to the conceptual approach, review
of staging manuals, and writing of the manuscript.
Dr Postmus: contributed to the review and revisions of the manuscript.
Dr Tanoue: contributed to the review and revisions of the manuscript.
Financial/nonfinancial disclosures: The authors have reported
to CHEST the following conflicts of interest: Dr Detterbeck is a
member of the International Association for the Study of Lung
Cancer International Staging Committee and a speaker in an educational program regarding lung cancer stage classification; both
activities are funded by Lilly Oncology (Lilly USA, LLC). He has
participated on a scientific advisory panel for Oncimmune (USA)
LLC; an external grant administration board for Pfizer, Inc; a multicenter study of a device for Medela; and formerly a multicenter
study of a device for DeepBreeze. Compensation for these activities is paid directly to Yale University. Drs Postmus and Tanoue
have reported that no potential conflicts of interest exist with any
companies/organizations whose products or services may be discussed in this article.
Role of Sponsors: The American College of Chest Physicians
was solely responsible for the development of these guidelines.
The remaining supporters played no role in the development
process. External supporting organizations cannot recommend
panelists or topics, nor are they allowed prepublication access to
the manuscripts and recommendations. Further details on the
Conflict of Interest Policy are available online at http://chestnet.
org.
Endorsements: This guideline is endorsed by the European
Society of Thoracic Surgeons, Oncology Nursing Society, American
Association for Bronchology and Interventional Pulmonology, and
the Society of Thoracic Surgeons.
Other contributions: The authors thank Ramon Rami-Porta,
MD, for his thoughtful critique during the development of this
article and review of the final manuscript.
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